Pharmacokinetics, Safety
Conditions
Keywords
Vagina, Film, Extended Release
Brief summary
This is a proof of concept study to determine whether an extended release vaginal film can deliver drug for seven days. Two film formulations containing MK-2048 which differ by dissolution and spreadability attributes will be compared for safety and pharmacokinetic outcomes.
Detailed description
This is a phase I randomized trial assessing the safety, acceptability, and pharmacokinetics of two formulations of MK-2048 vaginal film. While the primary objective is to evaluate the safety of the product, the overarching objective of this study is to provide proof of concept that an antiretroviral drug can be delivered in an extended release film formulation to provide drug delivery for 7 days or more after a single application. Forty eight women will be randomized with equal frequency to receive a single dose of a vaginal film containing MK-2048 (either the high Eudragit® or low Eudragit® formulation). The film will be inserted by a clinician on the day of enrollment. Vaginal swabs and plasma will be collected at days 0, 3, 5, 7, 10, 14 and 28 for all participants. On the day of enrollment, some participants may elect to participate in immediate post insertion sample collection (vaginal swab and plasma) at one or two time points within 6 hours of insertion. Genital biopsy samples and a rectal swab will be obtained on day 7, and cervicovaginal lavage will be collected at screening and days 14 and 28. The primary endpoint is the frequency of Grade 2 or higher adverse events. The secondary endpoints are: MK-2048 concentrations in plasma, cervical tissue homogenate, cervicovaginal lavage fluid, rectal and vaginal swab eluents; self-reported assessment of qualities of the experience with the films drawn from existing survey on microbicidal films, and general acceptability ratings drawn from market research methodology.
Interventions
COMBINATION_PRODUCTMK-2048 High Eudragit Vaginal Film
2 x 2 vaginal film containing 30 mg of MK-2048 and either 68.1 mg of ammonio methacrylate copolymer type B (Eudragit®)
COMBINATION_PRODUCTMK-2048 Low Eudragit Vaginal Film
2 x 2 vaginal film containing 30 mg of MK-2048 and 41.5 mg of ammonio methacrylate copolymer type B (Eudragit®)
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Hillier, Sharon, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Able and willing to provide written informed consent. * Willing to use an effective method of birth control throughout the duration of the study. Examples of effective methods include: hormonal methods (other than NuvaRing®), intrauterine device, bilateral tubal ligation, same sex partner, partner with a vasectomy, abstinence (defined as no vaginal sex for one month prior to screening). * Able and willing to provide adequate locator information * HIV-uninfected based on testing performed by study staff at screening * In general good health as determined by the site clinician * Agree to be sexually abstinent, including use of sex toys, from visit 2 (Enrollment) until visit 7 (7 days after the biopsy visit) and 48 hours prior to all study visits. * Agree to refrain from use of vaginal device or products (for example, lubricants, creams, suppositories) throughout participation in the study. Tampons may be used except between visit 5 (biopsy visit) and visit 7 (day 14). * Willingness to undergo all study-related assessments and follow all study-related procedures * At screening and enrollment, agrees not to participate in other research studies involving drugs, medical devices, or vaginal products while enrolled in this trial * Participants over the age of 21 (inclusive) must have documentation of a satisfactory Pap within three years prior to Enrollment consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (Dated November 2007) to the Division of Acquired Immune Deficiency Syndrome Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, or satisfactory evaluation with no treatment required of grade 1 or higher Pap results. If no documentation of a Pap smear can be provided, a Pap smear will be collected at the screening visit.
Exclusion criteria
* Menopause (as defined as amenorrhea for one year or more without an alternative etiology) * Hysterectomy * Participant report of any of the following: 1. Known adverse reaction to any of the study products (ever) 2. Non- therapeutic injection drug use in the 12 months prior to Screening 3. Surgical procedure involving the pelvis in the 60 days prior to enrollment (includes dilation and curettage or evacuation, and cryosurgery; does not include cervical biopsy for evaluation of an abnormal pap smear) 4. Participation in a drug, spermicide and/or microbicide study in the 30 days prior to enrollment 5. Currently pregnant or pregnancy within 42 days prior to enrollment 6. Currently lactating 7. Use of a diaphragm, NuvaRing®, or spermicide for contraception * Urogenital infection or suspected infection within 7 days of enrollment including: symptomatic candidiasis, trichomonas vaginalis, and symptomatic bacterial vaginosis; or cervical infection, including N. gonorrhoeae, C. trachomatis, or mucopurulent cervicitis; syphilis; herpes simplex virus lesions, or other sores (Note: seropositive herpes simplex virus without active lesions will not be excluded); acute pelvic inflammatory disease; urinary tract infection; recent exposure to a partner with N. gonorrhoeae, C. trachomatis, Trichomonas, syphilis, or non-gonorrheal urethritis * Antibiotic or antifungal therapy (vaginal or systemic) within 7 days of enrollment * As determined by the primary investigator, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine \*including poorly controlled diabetes), respiratory, immunologic disorder or infectious disease * Menses-like bleeding at the time of the Enrollment visit\* or expected menses-like bleeding within 14 days of the Enrollment visit (\*Women who have vaginal bleeding at the scheduled Enrollment visit may return at a different date to be re-examined and possibly enrolled provided they are still within the screening window and meet all criteria.) * Any condition that, in the opinion of the Investigator, would preclude provision of consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 2 or Higher Adverse Events | Through study completion, approximately 28 days | Number of participants who experience Grade 2 or higher adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Cervical Tissue Homogenate Concentration Versus Time Curve of MK-2048 | Through study completion, approximately 28 days | Area under the cervical tissue homogenate concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. |
| Area Under the Cervicovaginal Lavage Fluid Concentration Versus Time Curve of MK-2048 | Through study completion, approximately 28 days | Area under the cervicovaginal lavage fluid concentration versus time curve of MK-2048 reported as pg x day/mL |
| Area Under the Rectal Swab Eluent Concentration Versus Time Curve of MK-2048 | Through study completion, approximately 28 days | Area under the rectal swab eluent concentration versus time curve of MK-2048 reported as pg x day/mL |
| Area Under the Vaginal Swab Eluent Concentration Versus Time Curve of MK-2048 | Through study completion, approximately 28 days | Area under the vaginal swab eluent concentration versus time curve of MK-2048 reported as ng x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. |
| Area Under the Plasma Concentration Versus Time Curve of MK-2048 | Through study completion, approximately 28 days | Area under the plasma concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 plasma concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Nugent Score | Through study completion, approximately 28 days | Mean change in the Nugent score as determined from vaginal smears. Nugent scores range from 0 to 10; 0 indicates a Lactobacillus-dominant microbiome while a score of 10 indicates a microbiome dominated by bacterial vaginosis-associated bacteria. Nugent scores were assessed at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. The mean change was estimated from a mixed effects linear regression model and is defined as the average change between each post-insertion time point and the pre-insertion time point. |
| Human Immunodeficiency Virus-1 p24 Core Protein Titer in Cervical Biopsies | Through study completion, approximately 28 days | Human Immunodeficiency Virus-1 infection of cervical biopsies as defined as titer of the HIV-1 p24 core protein measured by ELISA and expressed as log10 pg/mL per mg of tissue |
| Median Fold Change in Percent Inhibition of Human Immunodeficiency Virus-1 Replication in Cervicovaginal Lavage Fluid | Through study completion, approximately 28 days | Median fold change in in-vitro anti-human immunodeficiency virus-1 activity in cervicovaginal lavage fluid determined by the TZM-bl assay and defined as percent inhibition of human immunodeficiency virus-1 infection by luciferase for a single round of replication measured at day 28 divided by percent inhibition measured at baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Eudragit MK-2048 Vaginal Film Single use of 2 x 2 vaginal film containing 30 mg of MK-2048 and 68.1 mg of ammonio methacrylate copolymer type B (Eudragit®).
MK-2048 High Eudragit Vaginal Film: 2 x 2 vaginal film containing 30 mg of MK-2048 and 68.1 mg of ammonio methacrylate copolymer type B (Eudragit®) | 25 |
| Low Eudragit MK-2048 Vaginal Film Single use of 2 x 2 vaginal film containing 30 mg of MK-2048 and 41.5 mg of ammonio methacrylate copolymer type B (Eudragit®).
MK-2048 Low Eudragit Vaginal Film: 2 x 2 vaginal film containing 30 mg of MK-2048 and 41.5 mg of ammonio methacrylate copolymer type B (Eudragit®) | 12 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Cervical biopsy not performed since participant did not refrain from sexual activity | 1 | 0 |
Baseline characteristics
| Characteristic | High Eudragit MK-2048 Vaginal Film | Low Eudragit MK-2048 Vaginal Film | Total |
|---|---|---|---|
| Age, Continuous | 26.6 years STANDARD_DEVIATION 6.9 | 28.2 years STANDARD_DEVIATION 5.5 | 27.2 years STANDARD_DEVIATION 6.5 |
| Has current sexual partner | 16 Participants | 7 Participants | 23 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Bi-/multi-racial | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic, not otherwise specified | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic, white | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Non-Hispanic, black | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Non-Hispanic, white | 15 Participants | 8 Participants | 23 Participants |
| Region of Enrollment United States | 25 participants | 12 participants | 37 participants |
| Sex: Female, Male Female | 25 Participants | 12 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 12 |
| other Total, other adverse events | 17 / 25 | 12 / 12 |
| serious Total, serious adverse events | 0 / 25 | 0 / 12 |
Outcome results
Primary
Number of Participants With Grade 2 or Higher Adverse Events
Number of participants who experience Grade 2 or higher adverse events
Time frame: Through study completion, approximately 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Number of Participants With Grade 2 or Higher Adverse Events | 2 Participants |
| Low Eudragit MK-2048 Vaginal Film | Number of Participants With Grade 2 or Higher Adverse Events | 5 Participants |
p-value: 0.025Fisher Exact
Secondary
Area Under the Cervical Tissue Homogenate Concentration Versus Time Curve of MK-2048
Area under the cervical tissue homogenate concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion.
Time frame: Through study completion, approximately 28 days
Population: MK 2048 levels in all tissue homogenate samples were below the limit of quantitation for the assay. Therefore, the area under the curve could not be calculated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Area Under the Cervical Tissue Homogenate Concentration Versus Time Curve of MK-2048 | NA pg x day/mL |
| Low Eudragit MK-2048 Vaginal Film | Area Under the Cervical Tissue Homogenate Concentration Versus Time Curve of MK-2048 | NA pg x day/mL |
Secondary
Area Under the Cervicovaginal Lavage Fluid Concentration Versus Time Curve of MK-2048
Area under the cervicovaginal lavage fluid concentration versus time curve of MK-2048 reported as pg x day/mL
Time frame: Through study completion, approximately 28 days
Population: Data not collected
Secondary
Area Under the Plasma Concentration Versus Time Curve of MK-2048
Area under the plasma concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 plasma concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion.
Time frame: Through study completion, approximately 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Area Under the Plasma Concentration Versus Time Curve of MK-2048 | 1370 pg x day/mL |
| Low Eudragit MK-2048 Vaginal Film | Area Under the Plasma Concentration Versus Time Curve of MK-2048 | 1873 pg x day/mL |
p-value: 0.47Wilcoxon (Mann-Whitney)
Secondary
Area Under the Rectal Swab Eluent Concentration Versus Time Curve of MK-2048
Area under the rectal swab eluent concentration versus time curve of MK-2048 reported as pg x day/mL
Time frame: Through study completion, approximately 28 days
Population: Data not collected
Secondary
Area Under the Vaginal Swab Eluent Concentration Versus Time Curve of MK-2048
Area under the vaginal swab eluent concentration versus time curve of MK-2048 reported as ng x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion.
Time frame: Through study completion, approximately 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Area Under the Vaginal Swab Eluent Concentration Versus Time Curve of MK-2048 | 543608 ng x day/mL |
| Low Eudragit MK-2048 Vaginal Film | Area Under the Vaginal Swab Eluent Concentration Versus Time Curve of MK-2048 | 1112355 ng x day/mL |
p-value: 0.67Wilcoxon (Mann-Whitney)
Other Pre-specified
Human Immunodeficiency Virus-1 p24 Core Protein Titer in Cervical Biopsies
Human Immunodeficiency Virus-1 infection of cervical biopsies as defined as titer of the HIV-1 p24 core protein measured by ELISA and expressed as log10 pg/mL per mg of tissue
Time frame: Through study completion, approximately 28 days
Population: All participants with a cervical biopsy sample taken. Two participants in the low Eudragit arm did not have cervical biopsies performed due to product discontinuation. One participant in the high Eudragit arm did not have a cervical biopsy collected due to safety concerns since she did not remain sexually abstinence prior to the visit and one participant's biopsy p24 results are not evaluable due to a lab processing error.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Human Immunodeficiency Virus-1 p24 Core Protein Titer in Cervical Biopsies | 96.0 log10 pg/mL |
| Low Eudragit MK-2048 Vaginal Film | Human Immunodeficiency Virus-1 p24 Core Protein Titer in Cervical Biopsies | 543.5 log10 pg/mL |
p-value: 0.09Wilcoxon (Mann-Whitney)
Other Pre-specified
Mean Change in Nugent Score
Mean change in the Nugent score as determined from vaginal smears. Nugent scores range from 0 to 10; 0 indicates a Lactobacillus-dominant microbiome while a score of 10 indicates a microbiome dominated by bacterial vaginosis-associated bacteria. Nugent scores were assessed at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. The mean change was estimated from a mixed effects linear regression model and is defined as the average change between each post-insertion time point and the pre-insertion time point.
Time frame: Through study completion, approximately 28 days
Population: All participants who had Nugent scores assessed at enrollment and at one or more follow-up visits. The 2 women who discontinued product in the low Eudragit arm were only followed for safety and did not have urogenital samples collected beyond the enrollment visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Mean Change in Nugent Score | -0.35 units on a scale |
| Low Eudragit MK-2048 Vaginal Film | Mean Change in Nugent Score | -0.62 units on a scale |
p-value: 0.65Mixed Models Analysis
p-value: 0.24Mixed Models Analysis
p-value: 0.27Mixed Models Analysis
Other Pre-specified
Median Fold Change in Percent Inhibition of Human Immunodeficiency Virus-1 Replication in Cervicovaginal Lavage Fluid
Median fold change in in-vitro anti-human immunodeficiency virus-1 activity in cervicovaginal lavage fluid determined by the TZM-bl assay and defined as percent inhibition of human immunodeficiency virus-1 infection by luciferase for a single round of replication measured at day 28 divided by percent inhibition measured at baseline.
Time frame: Through study completion, approximately 28 days
Population: All participants with a cervical biopsy sample taken. Two participants in the low Eudragit arm did not have cervical biopsies performed due to product discontinuation. One participant in the high arm also did not have a cervical biopsy collected due to safety concerns since she did not refrain from sexual activity prior to the visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Eudragit MK-2048 Vaginal Film | Median Fold Change in Percent Inhibition of Human Immunodeficiency Virus-1 Replication in Cervicovaginal Lavage Fluid | 1.01 ratio |
| Low Eudragit MK-2048 Vaginal Film | Median Fold Change in Percent Inhibition of Human Immunodeficiency Virus-1 Replication in Cervicovaginal Lavage Fluid | .92 ratio |
p-value: 0.51Wilcoxon (Mann-Whitney)